1. Field of the Invention
This invention relates to the field of regulation of expression of genes and, specifically, to the regulation and activation of genes by the transcription factor, NF-IL6/LAP.
2. Description of Related Art
Many eukaryotic genes are regulated in an inducible, cell type-specific or constitutive manner. There are different types of structural elements which are involved in the regulation of gene expression. There are cis-acting elements, located in the proximity of, or within, genes which serve to bind sequence-specific DNA binding proteins or trans-acting factors. The binding of proteins to DNA is responsible for the initiation, maintenance, or down-regulation of transcription of genes.
The cis-acting elements which control genes are called promoters, enhancers or silencers. Promoters are positioned next to the start site of transcription and function in an orientation-dependent manner, while enhancer and silencer elements, which modulate the activity of promoters, are flexible with respect to their orientation and distance to the start site of transcription.
Extracellular signals modulate the activity of many types of transcription factors. One important group of signal-regulated transcription factors are the BZip proteins, named because of their conserved basic (B) and leucine zipper (Zip) domains that are required for DNA binding and dimerization, respectively. Some well-studied examples of this family of transcription activator proteins include the AP-1/jun/fos family of transcription factors and CREB/ATF proteins which bind to the TPA (12-O-tetradecanoylphorbol-13-acetate) response element and cyclic AMP (cAMP) response element (CRE), respectively. Regulation by BZip proteins can involve a variety of complex mechanisms—transcriptional, temporal and post-translational—that affect the level and the repertoire of the factors expressed in a given cell, as well as their DNA binding and transcriptional activation functions.
NF-IL6/LAP (nuclear factor-interleukin 6/lymphokine activating protein) is a member of the bZIP family of transcriptional activators. NF-IL6/LAP protein is highly enriched in liver nuclei, where it has been implicated as a major regulator of acute-phase response. It is induced by interleukin-6 (IL-6) and other inflammatory mediators. NF-IL6/LAP is also involved in the activation of the IL-6 promoter in response to IL-1 and bacterial lipopolysaccharide (LPS). NF-IL6/LAP is involved in the induction of several cytokine genes including interleukin 6 (IL-6), interleukin 8 (IL-8), granulocyte-colony stimulating factor (G-CSF) and tumor necrosis factor alpha (TNF-α). These genes contain cis-acting elements which include a NF-IL6/LAP recognition sequence.
For many years, various drugs have been tested for their ability to alter the expression of genes or the translation of their messages into protein products. One problem with existing drug therapy is that it tends to act indiscriminately and affect healthy cells as well as neoplastic cells. This is a major problem with many forms of chemotherapy where there are severe side effect primarily due to the action of toxic drugs on healthy cells.
In view of the foregoing, there is a need to identify specific targets in the abnormal cell which are associated with the overexpression of genes whose expression products are implicated in cell proliferatve disorders, in order to decrease potential negative effect on healthy cells. The present invention provides such a target.